The pharmacological agents calcium antagonists of the dihydropyridine type and .beta.-adrenoreceptor antagonists are widely used in the treatment of cardiovascular disorders.
The mentioned dihydropyridines, e.g. felodipine, nifedipine and nitrendipine, are commonly used in the treatment of cardiovascular disorders like arterial hypertension and ischemic heart disease. The dihydropyridines reduce vascular resistance and load of the heart through a direct effect on the smooth muscles of the blood vessels. The dihydropyridines are characterized by an extremely low solubility in water and for such drugs a low and variable extent of absorption is often seen as the dissolution of the drug in vivo may be rate-limiting.
Several ways to increase drug absorption have been described in the prior litterature. One way is described in No. DE-A-3024858, where a sparingly soluble substituted dihydropyridine, nicardipine, is used in its amorphous form in order to obtain increased absorption of the active compound from the intestine. Another way is described in No. EP-A-47899, where very small crystals of a practically insoluble dihydropyridine, nifedipine, have been used in order to increase the extent of the bioavailability. These methods and others are also described in "Techniques of solubilization of drugs", Ed S. H. Yalkowsky in Drugs and the pharmaceutical sciences, Vol 12. Of particular relevance to the present invention is that surfactant solubilizing agents may be employed in order to increase the bioavailability of the drugs with very low solubility. It is stated that the improvement of absorption properties can be ascribed to three processes: (1) increased wetting (2) increased permeability of membranes and (3) solubilization.
In vivo, the plasma concentration versus time profile after administration of dihydropyridine conventional tablets is characterized by high peak concentrations and comparatively low trough levels. The blood pressure response mirrors the plasma concentration curve, i.e. there is a pronounced effect at the time of the peak and a much less effect after 24 hours. Accordingly, a conventional tablet is not optimal for once daily administration and the more even plasma concentrations produced by a controlled release preparation of high quality would be preferred.
Conventionally, controlled and extended release is achieved by controlling dissolution and/or diffusion of medicament from the dosage form. Several materials are employed for this purpose e.g waxes, fatty materials, polymers, natural, synthetic and semisynthetic gums. Among the gums, hydroxypropyl methylcellulose (HPMC) constitutes an important class because of its pH-independent properties as well as its semisynthetic origin. A review of cellulose ethers in hydrophilic matrices for oral controlled release dosage forms is given by Alderman D.A. Int.J.Pharm. Tech. & Prod. Mfr (1984), 5(3) 1-9. The chemical treatment of HPMC to generate a desired constitution and the use of these qualities are disclosed in U.S. Pat. Nos. 3,870,790, 4,226,849, 4,357,469 and 4,369,172. SE-A-8008646-5 describes a combination of HPMC and hydroxypropyl cellulose which is used to control the release rate of a pharmaceutically active compound.
When a hydrophilic matrix is used the soluble polymer forms a gelatinous layer around the tablet after exposure to gastro-intestinal fluids or saliva. The release of the drug is limited by the rate of water penetration into, and diffusion of drug through, the gel formed (Bamba et al. Int.J.Pharm. (1979),2,307). Erosion of the gel structure is also an important release mechanism of a drug from the system. The polymers used have to hydrate rapidly in order to protect the tablet from fast dissintegration (Alderman 1984).
Drugs with a very low solubility in water may be poorly absorbed from the gastro-intestinal tract due to incomplete or slow dissolution. Consequently it is difficult to increase the duration of effect through a controlled slow dissolution of such a drug without lowering the bioavailability (Bogentoft C and Sjogren J, Towards Better Safety of Drugs and Pharmaceutical Products, Editor D.D. Breimer, 1980 Elsevier/North Holland Biomedical Press).
The .beta.-adrenoreceptor antagonists block the adrenergic stimulation of the heart and thus reduce the oxygen demand of the cardiac tissue. Apparently, this explains their beneficial effects in angina pectoris and cardioprotective action in myocardial infarction. In addition, .beta.-adrenoreceptor antagonists normalize blood pressure in a large proportion of patients with arterial hypertension which probably is due to an additional action on the control of peripheral resistance to blood-flow. For patients treated with .beta.-adrenoreceptor antagonists for cardiovascular disorders it is advantageous to have a constant concentration of the administered drug in the blood. For dosage once a day the .beta.-adrenoreceptor antagonist metoprolol has been incorporated in controlled release tablets of the insoluble matrix type, e.g. Durules.RTM.. However, the drug release from the matrix tablets is not satisfying as about 50 % of the dose is released within a few hours after administration. For a drug like metoprolol with a comparatively short half-life a slower release rate is required in order to obtain even plasma concentrations over 24 hours. A constant release of metoprolol over 20-24 hours would be preferred. A preparation of metoprolol with such properties is described in No. EP-A-220 143.
It has been shown that a combination of a .beta.-adrenoreceptor antagonist and a vasodilating dihydropyridine is of advantage in many hypertensive patients since the two agents have synergistic effects (Hansson BG et al, Drugs 1985:29 (suppl 2); 131-135, Eggerston R and Hansson L Eur. J. Clin. Pharmacol 1982:21;389-390). In addition to the synergistic effects, a co-administration offers advantages regarding decrease in unwanted reflex counteractions elicited by either drug when administered alone (Dean S. and Kendall M. J. Eur. J. Clin. Pharmacol 1983:24;1-5).
Immediate release solid dosage forms of the fixed combination of a dihydropyridine derivative and a .beta.-adrenoreceptor antagonist with improved bioavailability are described in No. EP-A-163984.
However, a fixed combination of the two drugs in a preparation producing reproducible and even plasma concentrations of both drugs over the dosage interval after once daily administration has not been available. The large difference in physical-chemical properties between the two drugs makes it extremely difficult to obtain a suitable preparation based on conventional controlled release systems. A controlled release preparation of the two drugs would improve therapy through less frequent administration and improved patient compliance, (cf Hayes R. B. et al. Clin.Pharm. Ther (1977), 22, p. 125-130) may be obtained with controlled-release dosage forms. Although there has been a need for a controlled release preparation, expressed as far back as in 1977, for a once daily administration of the two drugs, such a preparation has not been available until the present inventors developed the preparation described in the following text.